Abstract: The rate of incidence and mortality in Alzheimer?s Disease (AD) is at an all-time high and expected to continue rising, in part due to the accumulating aging population, placing an ever- increasing burden on families and our public health care system. Despite the efforts of many, all therapeutic endeavors to significantly alter disease progression have failed, thus underscoring our lack of understanding of underlying AD pathophysiology and the amenability of AD at clinical presentation, which is considered late stage. Thus, there is a critical need to identify early stage biomarkers and novel therapeutic targets to expand treatment options and enable early diagnosis. We will address these issues via analyzing AD plasma derived cell-free DNA (cfDNA), which harbors cell-type specific nucleosome signatures and transcription factor footprinting patterns, to identify distinctive markers predicting disease stage and dysregulated pathways. This will be accomplished by deeply sequencing synthesized cfDNA libraries, as demonstrated by our preliminary experiments, using archived human plasma from (a)symptomatic AD patients enrolled in the Baltimore Longitudinal Study of Aging, and comprehensively assessing differences among the epigenetic state of genes across samples. This integrative analysis allows for the discovery of epigenetic biomarkers unique to AD stage and the identification of novel dysregulated pathways playing a role in AD progression. Our proposed work will profoundly improve clinical trial design, as it allows for patient stratification and refined patient population selectivity. Additionally, this work will provide a non-invasive screening tool for early AD diagnosis. Ultimately, this work will identify novel therapeutic targets and open new areas of research as these constituents and pathways are identified.